DE2236930A1 - PROCESS FOR THE PRODUCTION OF DESMOSTEROL - Google Patents
PROCESS FOR THE PRODUCTION OF DESMOSTEROLInfo
- Publication number
- DE2236930A1 DE2236930A1 DE2236930A DE2236930A DE2236930A1 DE 2236930 A1 DE2236930 A1 DE 2236930A1 DE 2236930 A DE2236930 A DE 2236930A DE 2236930 A DE2236930 A DE 2236930A DE 2236930 A1 DE2236930 A1 DE 2236930A1
- Authority
- DE
- Germany
- Prior art keywords
- desmosterol
- mixture
- cholesterol
- hydroxy
- chromatography
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Ceased
Links
- BDCFUHIWJODVNG-UHFFFAOYSA-N Desmosterol Natural products C1C=C2CC(O)C=CC2(C)C2C1C1CCC(C(C)CCC(CC)C(C)C)C1(C)CC2 BDCFUHIWJODVNG-UHFFFAOYSA-N 0.000 title claims description 24
- AVSXSVCZWQODGV-DPAQBDIFSA-N desmosterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@@H](CCC=C(C)C)C)[C@@]1(C)CC2 AVSXSVCZWQODGV-DPAQBDIFSA-N 0.000 title claims description 24
- 238000000034 method Methods 0.000 title claims description 19
- 238000004519 manufacturing process Methods 0.000 title description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 18
- 239000000203 mixture Substances 0.000 claims description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 16
- 238000004587 chromatography analysis Methods 0.000 claims description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 10
- 229940068065 phytosterols Drugs 0.000 claims description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 239000000047 product Substances 0.000 claims description 8
- 239000007858 starting material Substances 0.000 claims description 8
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims description 6
- 229910052710 silicon Inorganic materials 0.000 claims description 6
- 239000010703 silicon Substances 0.000 claims description 6
- WRYNUJYAXVDTCB-UHFFFAOYSA-M acetyloxymercury Chemical compound CC(=O)O[Hg] WRYNUJYAXVDTCB-UHFFFAOYSA-M 0.000 claims description 5
- 238000006243 chemical reaction Methods 0.000 claims description 5
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 4
- 230000018044 dehydration Effects 0.000 claims description 4
- 238000006297 dehydration reaction Methods 0.000 claims description 4
- 238000000605 extraction Methods 0.000 claims description 4
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 claims description 4
- 229910052708 sodium Inorganic materials 0.000 claims description 4
- 239000011734 sodium Substances 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 241000196324 Embryophyta Species 0.000 claims description 3
- 244000048879 Funtumia elastica Species 0.000 claims description 3
- 150000001242 acetic acid derivatives Chemical class 0.000 claims description 3
- 239000011541 reaction mixture Substances 0.000 claims description 3
- 238000001179 sorption measurement Methods 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- 241000208327 Apocynaceae Species 0.000 claims description 2
- 241000983398 Holarrhena Species 0.000 claims description 2
- 238000002425 crystallisation Methods 0.000 claims description 2
- 230000008025 crystallization Effects 0.000 claims description 2
- 238000001704 evaporation Methods 0.000 claims description 2
- 230000007935 neutral effect Effects 0.000 claims description 2
- 230000020477 pH reduction Effects 0.000 claims description 2
- 229910001961 silver nitrate Inorganic materials 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims 2
- 230000021736 acetylation Effects 0.000 claims 1
- 238000006640 acetylation reaction Methods 0.000 claims 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims 1
- 229910052782 aluminium Inorganic materials 0.000 claims 1
- 239000007795 chemical reaction product Substances 0.000 claims 1
- 238000001035 drying Methods 0.000 claims 1
- 238000002955 isolation Methods 0.000 claims 1
- 239000003921 oil Substances 0.000 claims 1
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 12
- 230000015572 biosynthetic process Effects 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 8
- 235000012000 cholesterol Nutrition 0.000 description 6
- 150000003431 steroids Chemical class 0.000 description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000011710 vitamin D Substances 0.000 description 3
- 229940046008 vitamin d Drugs 0.000 description 3
- XZEUYTKSAYNYPK-UHFFFAOYSA-N 3beta-29-Norcycloart-24-en-3-ol Natural products C1CC2(C)C(C(CCC=C(C)C)C)CCC2(C)C2CCC3C(C)C(O)CCC33C21C3 XZEUYTKSAYNYPK-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- RRTBTJPVUGMUNR-UHFFFAOYSA-N Cycloartanol Natural products C12CCC(C(C(O)CC3)(C)C)C3C2(CC)CCC2(C)C1(C)CCC2C(C)CCCC(C)C RRTBTJPVUGMUNR-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- HVXLSFNCWWWDPA-UHFFFAOYSA-N Isocycloartenol Natural products C1CC(O)C(C)(C)C2C31CC13CCC3(C)C(C(CCCC(C)=C)C)CCC3(C)C1CC2 HVXLSFNCWWWDPA-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- HXQRIQXPGMPSRW-UHZRDUGNSA-N Pollinastanol Natural products O[C@@H]1C[C@H]2[C@@]3([C@]4([C@H]([C@@]5(C)[C@@](C)([C@H]([C@H](CCCC(C)C)C)CC5)CC4)CC2)C3)CC1 HXQRIQXPGMPSRW-UHZRDUGNSA-N 0.000 description 2
- 229930003316 Vitamin D Natural products 0.000 description 2
- QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Natural products C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C/C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-XFEUOLMDSA-N 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- ONQRKEUAIJMULO-YBXTVTTCSA-N cycloartenol Chemical compound CC(C)([C@@H](O)CC1)[C@H]2[C@@]31C[C@@]13CC[C@]3(C)[C@@H]([C@@H](CCC=C(C)C)C)CC[C@@]3(C)[C@@H]1CC2 ONQRKEUAIJMULO-YBXTVTTCSA-N 0.000 description 2
- YNBJLDSWFGUFRT-UHFFFAOYSA-N cycloartenol Natural products CC(CCC=C(C)C)C1CCC2(C)C1(C)CCC34CC35CCC(O)C(C)(C)C5CCC24C YNBJLDSWFGUFRT-UHFFFAOYSA-N 0.000 description 2
- FODTZLFLDFKIQH-UHFFFAOYSA-N cycloartenol trans-ferulate Natural products C1=C(O)C(OC)=CC(C=CC(=O)OC2C(C3CCC4C5(C)CCC(C5(C)CCC54CC53CC2)C(C)CCC=C(C)C)(C)C)=C1 FODTZLFLDFKIQH-UHFFFAOYSA-N 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 238000007127 saponification reaction Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 235000013311 vegetables Nutrition 0.000 description 2
- 235000019166 vitamin D Nutrition 0.000 description 2
- 150000003710 vitamin D derivatives Chemical class 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- OILXMJHPFNGGTO-UHFFFAOYSA-N (22E)-(24xi)-24-methylcholesta-5,22-dien-3beta-ol Natural products C1C=C2CC(O)CCC2(C)C2C1C1CCC(C(C)C=CC(C)C(C)C)C1(C)CC2 OILXMJHPFNGGTO-UHFFFAOYSA-N 0.000 description 1
- RQOCXCFLRBRBCS-UHFFFAOYSA-N (22E)-cholesta-5,7,22-trien-3beta-ol Natural products C1C(O)CCC2(C)C(CCC3(C(C(C)C=CCC(C)C)CCC33)C)C3=CC=C21 RQOCXCFLRBRBCS-UHFFFAOYSA-N 0.000 description 1
- OBQGEVWZIBSVFW-UHFFFAOYSA-N (3beta, 20S)-Cholesta-5, 24-dien-3-ol, 9CI Natural products C1C=C2CC(OC(C)=O)CCC2(C)C2C1C1CCC(C(CCC=C(C)C)C)C1(C)CC2 OBQGEVWZIBSVFW-UHFFFAOYSA-N 0.000 description 1
- WIGIZIANZCJQQY-UHFFFAOYSA-N 4-ethyl-3-methyl-N-[2-[4-[[[(4-methylcyclohexyl)amino]-oxomethyl]sulfamoyl]phenyl]ethyl]-5-oxo-2H-pyrrole-1-carboxamide Chemical compound O=C1C(CC)=C(C)CN1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCC(C)CC2)C=C1 WIGIZIANZCJQQY-UHFFFAOYSA-N 0.000 description 1
- OQMZNAMGEHIHNN-UHFFFAOYSA-N 7-Dehydrostigmasterol Natural products C1C(O)CCC2(C)C(CCC3(C(C(C)C=CC(CC)C(C)C)CCC33)C)C3=CC=C21 OQMZNAMGEHIHNN-UHFFFAOYSA-N 0.000 description 1
- UPEZCKBFRMILAV-JNEQICEOSA-N Ecdysone Natural products O=C1[C@H]2[C@@](C)([C@@H]3C([C@@]4(O)[C@@](C)([C@H]([C@H]([C@@H](O)CCC(O)(C)C)C)CC4)CC3)=C1)C[C@H](O)[C@H](O)C2 UPEZCKBFRMILAV-JNEQICEOSA-N 0.000 description 1
- DNVPQKQSNYMLRS-NXVQYWJNSA-N Ergosterol Natural products CC(C)[C@@H](C)C=C[C@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)CC[C@]4(C)[C@@H]3CC[C@]12C DNVPQKQSNYMLRS-NXVQYWJNSA-N 0.000 description 1
- 241000983373 Funtumia Species 0.000 description 1
- 241000282596 Hylobatidae Species 0.000 description 1
- 241000237852 Mollusca Species 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 241000206572 Rhodophyta Species 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- OBQGEVWZIBSVFW-MFAYAQHLSA-N [(3s)-10,13-dimethyl-17-(6-methylhept-5-en-2-yl)-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1h-cyclopenta[a]phenanthren-3-yl] acetate Chemical compound C1C=C2C[C@@H](OC(C)=O)CCC2(C)C2C1C1CCC(C(CCC=C(C)C)C)C1(C)CC2 OBQGEVWZIBSVFW-MFAYAQHLSA-N 0.000 description 1
- UPEZCKBFRMILAV-UHFFFAOYSA-N alpha-Ecdysone Natural products C1C(O)C(O)CC2(C)C(CCC3(C(C(C(O)CCC(C)(C)O)C)CCC33O)C)C3=CC(=O)C21 UPEZCKBFRMILAV-UHFFFAOYSA-N 0.000 description 1
- 230000001749 antrachitic effect Effects 0.000 description 1
- -1 boron sodium hydride Chemical compound 0.000 description 1
- 210000003837 chick embryo Anatomy 0.000 description 1
- 239000004927 clay Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- UPEZCKBFRMILAV-JMZLNJERSA-N ecdysone Chemical compound C1[C@@H](O)[C@@H](O)C[C@]2(C)[C@@H](CC[C@@]3([C@@H]([C@@H]([C@H](O)CCC(C)(C)O)C)CC[C@]33O)C)C3=CC(=O)[C@@H]21 UPEZCKBFRMILAV-JMZLNJERSA-N 0.000 description 1
- DNVPQKQSNYMLRS-SOWFXMKYSA-N ergosterol Chemical compound C1[C@@H](O)CC[C@]2(C)[C@H](CC[C@]3([C@H]([C@H](C)/C=C/[C@@H](C)C(C)C)CC[C@H]33)C)C3=CC=C21 DNVPQKQSNYMLRS-SOWFXMKYSA-N 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 229940058690 lanosterol Drugs 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 238000000622 liquid--liquid extraction Methods 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 238000004537 pulping Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
Description
"Verfahren zur Herstellung von Desmosterol""Process for the production of Desmosterol"
Die Erfindung richtet sich auf ein Verfahren zur Herstellung von Desmosterol der Formel Ο^Έ,,Ο und seiner Derivate aus pflanzlichen Ausgangsprodukten.The invention is directed to a process for the production of desmosterol of the formula Ο ^ Έ ,, Ο and its derivatives from vegetable starting materials.
Es ist bekannt, daß Desmosterol eine bedeutende' Rolle bei der Biosynthese des Cholesterin beim Tier spielt und zwar als labiles Zwischenprodukt (W.M. Stokes, W.A. Fish et P.C. Hickel, J. Biol Chem. 1956, 220, 415; W.M.. Stokes et coil. ibid. 1958, 252, 347; J. Avignan et coll. J.Biol. Chem. 1960, 2^5, 3123). Die Autoren haben minimale Mengen aus Embryonen von Küken, aus der Haut der Ratte, aus dem Serum, aus der Leber und anderen tierischen Geweben isoliert.It is known that desmosterol plays an important role in the biosynthesis of cholesterol in animals, namely as a labile intermediate product (WM Stokes, WA Fish et PC Hickel, J. Biol Chem. 1956, 220, 415; WM. Stokes et coil. ibid. 1958, 252 , 347; J. Avignan et coll. J.Biol. Chem. 1960, 2 ^ 5, 3123). The authors isolated minimal amounts from chick embryos, rat skin, serum, liver, and other animal tissues.
Das Desmosterol wurde ebenfalls isoliert aus verschiedenen marinen Mollusken (Fagerlund et Idler, J.Amer. Chem. Soc. 1957, 22* Desmosterol was also isolated from various marine mollusks (Fagerlund et Idler, J.Amer. Chem. Soc. 1957, 22 *
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6473) und kürzlich aus Rotalgen (Gibbons, Goad and Goodwin, Phytochemistry, 1967, 6_, 677; D.R.Idler, A.Saito et P.Wiseman, Steroids, 1968, JJ., 465).6473) and recently from red algae (Gibbons, Goad and Goodwin, Phytochemistry, 1967, 6_, 677; D.R. Idler, A. Saito and P. Wiseman, Steroids, 1968, JJ., 465).
Eine Teilsynthese wurde realisiert (Fagerlund et Idler, loc.cit.; Bermann et Dusza, J. Org. Chem. 1958, 2J5, 459), jedoch ist das Produkt außerordentlich teuer mangels ausreichendem und marktfähigen Ausgangsmaterial.A partial synthesis was carried out (Fagerlund et Idler, loc. Cit .; Bermann et Dusza, J. Org. Chem. 1958, 2J5, 459), but that is Product extremely expensive due to a lack of sufficient and marketable starting material.
Indes liegt die besondere Bedeutung des Desmosterol vornehmlich darin, daß es in gleicher Weise als interessantes Ausgangsmaterial für die Teilsynthese verschiedener physiologisch aktiver Steroide in Betracht kommt, von denen zahlreiche in den letzten Jahren eine große Bedeutung erlangt haben (hormones du type ecdysone; hydroxy-25 vitamine D, ou 25 H.C.C. etc.).However, the particular importance of desmosterol lies primarily in the fact that it is an interesting starting material in the same way for the partial synthesis of various physiologically active steroids into consideration, numerous of which in the last Years have achieved great importance (hormones du type ecdysone; hydroxy-25 vitamine D, ou 25 H.C.C. etc.).
In der Tat hat im Gegensatz zum Cholesterin das übliche Ausgangsmaterial zur Synthese verschiedener Steroide (z.B. zur Synthese des Vitamin D,) in Form des Desmosterol eine wirksame Seitenkette (Δ2*In fact, in contrast to cholesterol, the usual starting material for the synthesis of various steroids (e.g. for the synthesis of vitamin D) in the form of desmosterol has an effective side chain (Δ 2 *
Wenn man beispielsweise die Synthese des Hydroxy-25-Vitamin D, oder 25 H.C.C. als biologisch aktive Form des Vitamin D^ und eine Substanz, deren antirachitische Wirksamkeit heute von der größten Bedeutung ist (J.A. Champbell, D.M. Squires et J.G. Babcock, Steroids, 1969, Jj5> 567) betrachtet, ist es schwierig, diese Synthese ausgehend von Cholesterol vorzunehmen. Dagegen istFor example, considering the synthesis of hydroxy-25-vitamin D, or 25 H.C.C. as a biologically active form of vitamin D ^ and a Substance whose antirachitic effectiveness is of the greatest importance today (J.A. Champbell, D.M. Squires et J.G. Babcock, Steroids, 1969, Jj5> 567), it is difficult to find these To make synthesis starting from cholesterol. Against it is
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das Desmosterol ein "besonders geeignetes Ausgangsmaterial. Die Synthese des ^ -Desmosterol ist "bekannt (T.J. Scallen, Research Communications, 1965, 2Λ_> 89)» "und die späteren Reaktionen sind gleichfalls bekannt aus der Serie des Δ'-Cholesterin und des Ergosterin.Desmosterol is a "particularly suitable starting material. The synthesis of ^ -desmosterol is" known (TJ Scallen, Research Communications, 1965, 2Λ_> 8 9) "" and the later reactions are also known from the series of Δ'-cholesterol and des Ergosterol.
Die Erfindung hat zur Aufgabe die Gewinnung des reinen Desmosterol und seiner Derivate aus einem reichlich vorhandenen pflanzlichen Ausgangsmaterial. Dieses Material wird insbesondere aus Pflanzen extrahiert, die von den Phanerogamen abstammen, insbesondere aus der Familie der Apocynaceen oder von den Gattungen Funtumia, Holarrhena und ähnlichen. Die Beschreibung nimmt Bezug auf Untersuchungen anhand von Körnern von Funtumia Elastica, obgleich analoge Ergebnisse auch von anderen Teilen der Pflanze erhältlich sind.The object of the invention is to obtain pure desmosterol and its derivatives from an abundant vegetable source. This particular material is made from Extracted plants derived from the phanerogams, in particular from the Apocynaceae family or from the genera Funtumia, Holarrhena, and the like. The description refers to investigations using grains of Funtumia Elastica, although analogous results are also available from other parts of the plant.
Gemäß der Erfindung wird ein besonders interessantes beständiges Derivat des Desmosterol gewonnen, vornehmlich das Hydroxy-25-Cholesterin sowie dessen Derivate. Es ist einerseits bekannt, daß das Desmosterol, selbst wenn es bei völliger Dunkelheit gehalten wird, sich innerhalb einiger Monate zersetzt (M.J. Thompson, J.N. Kaplanis et H.E. Vroma, Steroids, 1965, 551). Andererseits werden das Hydroxy-25-Cholesterin und seine Derivate als Ausgangsmaterial zur Synthese des 25 H.C.C. (J.W. Blunt & H.I1. de Luca, Biochemistry 1969, 8, 671-675), jedoch ist das Hydroxy-25-Cholesterin außerordentlich teuer (Steraloids, Inc., New York),According to the invention, a particularly interesting stable derivative of desmosterol is obtained, primarily hydroxy-25-cholesterol and its derivatives. On the one hand, it is known that desmosterol, even if kept in complete darkness, decomposes within a few months (MJ Thompson, JN Kaplanis et HE Vroma, Steroids, 1965, 551). On the other hand, hydroxy-25-cholesterol and its derivatives are used as a starting material for the synthesis of 25 HCC (JW Blunt & HI 1. De Luca, Biochemistry 1969, 8, 671-675), but hydroxy-25-cholesterol is extremely expensive (Steraloids , Inc., New York),
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Das erfindungsgemäße Verfahren wird im Folgenden erläutert, wobei die Besonderheiten ausschließlich im Rahmen der Erfindung liegen.The method according to the invention is explained below, the special features exclusively within the scope of the invention lie.
Die Körner von Funtumia Elastica werden geerntet, vorzugsweise bei völliger Vollreife, getrocknet, zermahlen und im neutralen Milieu behandelt, um durch ein Lösungsmittel die ölige Substanz zu extrahieren, die durch Natrium oder Kalium verseift wird. Darauf wird das verseifte Gemisch unter Rühren mit destilliertem Wasser verdünnt. Mit 20#iger Salzsäure wird bis zu einem pH-Wert von etwa 8 angesäuert und das Ganze in ein Äthyläther enthaltendes Dekantiergefäß gegeben. Fach erneutem Rühren und einer darauf folgenden Ruhezeit wird dekantiert. Man trennt die organische Schicht ab und extrahiert die wässrige Masse mit lthylather durch dreimalige Wiederholung der vorgenannten Verfahrensweise.The grains of Funtumia Elastica are harvested, preferably when fully ripe, dried, ground and treated in a neutral environment to remove the oily substance with a solvent extract, which is saponified by sodium or potassium. The saponified mixture is then distilled with stirring Water diluted. With 20 # hydrochloric acid is acidified to a pH value of about 8 and the whole thing in an ethyl ether containing Given to decanter. Tray again stirring and a subsequent rest period is decanted. Separate the organic Layer off and extract the aqueous mass with ethyl ether repeating the aforementioned procedure three times.
Die verschiedenen ätherischen Extrakte werden zusammengeführt, mit destilliertem Wasser gewaschen und dann auf wasserfreiem Natriumsulfat getrocknet. Dann wird die Äther-Lösung gefiltert und in einem Rotationsevaporator verdampft. Der verbleibende Rest ist unverseifbar und besteht aus Cycloartenol, nor-51-Lanosterol, Dehydro-24-Lophenol und anderen Phytosterolen.The various essential extracts are brought together, washed with distilled water and then dried over anhydrous sodium sulfate. Then the ether solution is filtered and evaporated in a rotary evaporator. The remainder is unsaponifiable and consists of cycloartenol, nor-51-lanosterol, Dehydro-24-lophenol and other phytosterols.
Das verseifte Gemisch kann gleichfalls nach Ansäuern in einem Gerät zur Flussig-Flüssig-Extraktlon im Aufstrom durch Äthyläther, Petroläther oder Hexan kontinuierlich extrahiert werden. The saponified mixture can also be extracted continuously after acidification in a device for liquid-liquid extraction in an upflow through ethyl ether, petroleum ether or hexane.
309807/1325309807/1325
223693Q223693Q
Der gesamte !inverseifbare Eest wird daraufhin auf Tonerde chromatographiert. Man trennt nacheinander das Cycloartenol, das Gemisch des Dehydro-24-Iiophenol und des nor-31-Isanosterol und schließlich das Gemisch der Phytosterole ab, welches■hauptsächlich Demosterol enthält. Zur Durchführung des erfindungsgemäßen Verfahrens und seiner einzelnen Schritte sind zahlreiche Varianten möglich.The entire inversifiable residue is then chromatographed on clay. The cycloartenol, the mixture of the dehydro-24-Iiophenol and the nor-31-Isanosterol and finally one separates one after the other the mixture of phytosterols, which ■ mainly demosterol contains. Numerous variants are possible for carrying out the method according to the invention and its individual steps.
Variante Aoption A
Das Gemisch der Phytosterole wird azetyliert tmd die gewonnen Azetate auf einer mit Silbernitrat imprägnierten Silisiumsäule chromatographiert oder aber den üblichen Abtrennverfahren unterzogen, die dem einschlägigen Fachmann bekannt sind* Anstelle dieses vergleichsweise langen und kostspieligen Verfahrens kann man das im Folgenden (Variante B) erläuterte Verfahren anwenden»The mixture of phytosterols is acetylated and extracted Acetates on a silicon column impregnated with silver nitrate chromatographed or subjected to the customary separation processes known to the person skilled in the art * Instead of this a comparatively long and costly procedure can be used as described in the following (variant B) »
Man nimmt eine Grobbearbeitung des Gemisches durch Breiiraing der Komponenten nach zwei Kategorien vors die Bestandteile mit ©iner Doppelbindung, die zunächst herausgelöst werdenp und die Bestandteile mit zwei Doppelbindungen» insbesondere das Desmosterol in Form des Azetats» welches anschließend herausgelöst wird,, Diese zweite Kategorie,der Anteile enthält bereits einen· sehr großen Anteil des Desmosterol in Form des Azetats»One takes a rough processing of the mixture by pulping the Components according to two categories in front of the constituents with a double bond, which are initially detached, and the constituents with two double bonds »in particular the desmosterol in Form of the acetate »which is then dissolved out, This second category, which already contains a · very large share Share of desmosterol in the form of acetate »
Dieses Gemisch von in Tetrahydrofuran in Lösung befindlichen Azetaten wird mit Quecksilberazetat behandelt und das Reaktionsgemisch darauf mit Bornatriumhydrid, reduziert« Nach Extraktion des organischen Produkts gewinnt man ein Gemisch von Anteilen? dasThis mixture of acetates in solution in tetrahydrofuran is treated with mercury acetate and the reaction mixture is then reduced with boron sodium hydride. After extraction of the organic product, a mixture of fractions is obtained . the
3:0 9 8 0 77 i3 2 S-.3: 0 9 8 0 77 i3 2 S-.
223693Q223693Q
in einer Adsorptionskolonne (Silizium od.dgl.) einer Chromatographie unterzogen wird. Anstelle dieser Maßnahme kann man auch das Verfahren, welches unten in der Variante C erläutert ist, anwenden.in an adsorption column (silicon or the like) of a chromatography is subjected. Instead of this measure, you can also use the method which is explained below in variant C, use.
Die Produkte, die nicht reagiert haben, werden zunächst gelöst, worauf man das Hydroxy-25-Cholesterin in Form des Monoazetats erhält. The products that did not react are first dissolved, whereupon the hydroxy-25-cholesterol is obtained in the form of the monoacetate.
Die Verseifung dieses Produkts führt zum Hydroxy-25-Cholesterin. Das Desmosterol wird in Form des Azetats durch Dehydrierung des Monoazetats des Hydroxy-25-Cholesterin gewonnen. Man reinigt es dann durch Kristallisation in Azeton.The saponification of this product leads to the hydroxy-25-cholesterol. The desmosterol is in the form of the acetate by dehydration of the Hydroxy-25 cholesterol monoacetate. It is then purified by crystallization in acetone.
Die Verseifung des Desmosteryl-Azetats führt zum Desmosterol.The saponification of the desmosteryl acetate leads to desmosterol.
Variante BVariant B
Man unterzieht das Gemisch der Phytosterole aus der ersten Chromatographie den anschließenden Verfahrensgangen, die den Zweck verfolgen, das Hydroxy-25-Cholesterin zu gewinnen.The mixture of phytosterols from the first chromatography is subjected the subsequent proceedings that serve the purpose pursue to gain the hydroxy-25 cholesterol.
Das Gemisch der Phytosterole wird in Tetrahydrofuran gelöst und die gewonnene Lösung gerührt oder geschüttelt, worauf man einen geringen Überschuß von Quecksilberazetat zusetzt. Man berücksichtigt den Reaktionsfortschritt durch periodische Chromatographie auf dünner Siliziumschicht. Fach Beendigung der Reaktion wird das reaktionsfähige Gemisch mit Natriumborhydrur reduziert« DieThe mixture of phytosterols is dissolved in tetrahydrofuran and the solution obtained is stirred or shaken, whereupon one small excess of mercury acetate added. One takes into account the progress of the reaction through periodic chromatography on a thin silicon layer. Tray will terminate the reaction the reactive mixture with sodium borohydrate reduced «The
'0 QvfcO ? .'.i 3 2c'0 QvfcO? . '. i 3 2c
223693Q223693Q
organische Schicht wird daraufhin abgetrennt, getrocknet und evapo-riert. Der Rückstand wird durch Benzol wiedergewonnen und auf einer Adsorptionssäule (Silizium od.dgl.) chromatographiert. Anstelle dieser Chromatographie kann man auch, wie oben, die unten erläuterte Variante C anwenden. Man behandelt die Kolonne mit dem Gemisch von Benzol und Äthylazetat. Zuletzt wird das Hydroxy-25-Cholesterin behandelt. Seine Dehydrierung, führt zum Desmosterol. - -The organic layer is then separated off, dried and evapo-ured. The residue is recovered with benzene and chromatographed on an adsorption column (silicon or the like). Instead of Variant C explained below can also be used in this chromatography, as above. The column is treated with the mixture of benzene and ethyl acetate. Last is the hydroxy-25 cholesterol treated. Its dehydration leads to desmosterol. - -
Variante .0Variant .0
Man unterläßt die Chromatographie auf der Siliziumsäule und verfährt auf folgende Weise. The chromatography on the silicon column is omitted and the following procedure is used.
Das reaktionsfähige Gemisch aus der Behandlung der Phytosterole mit Quecksilberazetat in Tetrahydrofuran, nach einer Reduktion durch Natriumborhydrat und nach Extraktion und Verdampfen des Lösungsmittels, wird durch Benzol warm behandelt bis zur völligen Lösung. Dann kühlt man die Lösung bei Umgebungstemperatur ab. Das Hydroxy-25-Cholesterin kristallisiert aus. Es wird abgefiltert. Die Benzol-Mutterlauge wird unter vermindertem Druck verdampft und der Niederschlag warm in Methylalkohol gelöst. Beim Abkühlen kristallisieren die Phytosterole, die nicht reagiert haben ebenso wie die anderen Produkte aus. Es wird wiederum abgefiltert. Die Methanol-Mutterlauge wird unter vermindertem Druck verdampft, und der Rest in Benzol warm gelöst. Beim Abkühlen kristallisiert eine weitere Menge Hydroxy-25-Cholesterin aus.The reactive mixture from the treatment of the phytosterols with mercury acetate in tetrahydrofuran, after a reduction by sodium borohydrate and, after extraction and evaporation of the solvent, is treated warm to complete by benzene Solution. The solution is then cooled at ambient temperature. The hydroxy-25-cholesterol crystallizes out. It is filtered out. The benzene mother liquor is evaporated under reduced pressure and the precipitate is dissolved warm in methyl alcohol. When it cools down, the phytosterols that have not reacted crystallize out, just like the other products. It will turn filtered out. The methanol mother liquor is evaporated under reduced pressure and the residue is dissolved in warm benzene. When cooling down Another amount of hydroxy-25-cholesterol crystallizes out.
309807/1325309807/1325
Diese Verfahrensgänge genügen im allgemeinen^ um annähernd das gesamte Hydroxy-25-Cholesterin des reaktionsfähigen Gemisches abzutrennen. These procedural steps generally suffice for almost all of them Separate hydroxy-25-cholesterol of the reactive mixture.
Man kann die Chromatographie der Varianten A und B zur Rückgewinnung des Restes an Hydroxy-25-Cholesterin der Mutterlaugen anwenden. One can use the chromatography of variants A and B for recovery of the rest of the hydroxy-25-cholesterol from the mother liquors.
Die Dehydrierung des Hydroxy-25-Cholesterin führt zu dem Desmosterol. The dehydration of the hydroxy-25-cholesterol leads to the desmosterol.
309807/1325309807/1325
Claims (10)
gewinnt.6. The method according to any one of claims 1 to 5, characterized in that the desmosterol contained in the phytosterol fraction by chromatography on an aluminum column
wins.
Gemisches der Phytosterole, Chromatographie der Azetate mit einer mit Silbernitrat od.dgl. imprägnierten Siliziumsäule, Reaktion des Azetatgemisches mit zwei Doppelbindungen mit
Quecksilberazetat in Tetrahydrofuran, Reduktion des Reaktionsproduktes und Extraktion des gewonnen Produkts sowie schließlich Chromatographie dieses Produktes mit Hilfe einer Adsorptionssäule ,gewinnt.7. The method according to any one of claims 1 to 6, characterized in that the derived from the desmosterol hydroxy-25-cholesterol in the form of the monoacetate by acetylation of the
Mixture of phytosterols, chromatography of the acetates with one with silver nitrate or the like. impregnated silicon column, reaction of the acetate mixture with two double bonds with
Mercury acetate in tetrahydrofuran, reduction of the reaction product and extraction of the product obtained and finally chromatography of this product using an adsorption column, wins.
das Gemisch der Phytosterole unmittelbar mit Quecksilberazetat behandelt, darauf durch Natriumborhydrat reduziert und
schließlich das Hydroxy-25-Cholesterol von dem Reaktionsgemisch durch Chromatographie auf einer Kolonne abtrennt-9. The method according to claim 7, characterized in that one
the mixture of phytosterols treated immediately with mercury acetate, then reduced by sodium borohydrate and
Finally, the hydroxy-25-cholesterol is separated from the reaction mixture by chromatography on a column.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| OA54321A OA04246A (en) | 1971-08-03 | 1971-08-03 | Process for the preparation of desmosterol. |
| OA54484 | 1972-02-03 | ||
| OA54483 | 1972-02-03 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE2236930A1 true DE2236930A1 (en) | 1973-02-15 |
Family
ID=27353950
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE2236930A Ceased DE2236930A1 (en) | 1971-08-03 | 1972-07-27 | PROCESS FOR THE PRODUCTION OF DESMOSTEROL |
Country Status (8)
| Country | Link |
|---|---|
| US (1) | US3803184A (en) |
| JP (1) | JPS5241260B2 (en) |
| BE (1) | BE787024A (en) |
| CH (1) | CH582714A5 (en) |
| DE (1) | DE2236930A1 (en) |
| FR (1) | FR2149796A5 (en) |
| GB (1) | GB1355272A (en) |
| NL (1) | NL7210355A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101270141B (en) * | 2008-04-16 | 2010-12-01 | 浙江大学 | Method for separating 24-dehydrogenation cholesterol and cholesterol |
Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4222949A (en) * | 1979-08-20 | 1980-09-16 | Eastman Kodak Company | Process for separating stigmasterol-derived products (II) |
| EP0053415B1 (en) * | 1980-12-02 | 1985-10-09 | Duphar International Research B.V | Method of isolating sterols in commercial quantities from sterol-containing material |
| JPH05226Y2 (en) * | 1985-05-27 | 1993-01-06 | ||
| AU2013259624B2 (en) | 2012-05-08 | 2017-10-19 | Lycera Corporation | Tetrahydro[1,8]naphthyridine sulfonamide and related compounds for use as agonists of RORy and the treatment of disease |
| JP2017507950A (en) | 2014-02-27 | 2017-03-23 | リセラ・コーポレイションＬｙｃｅｒａ Ｃｏｒｐｏｒａｔｉｏｎ | Adoptive cell therapy using retinoic acid receptor-related orphan receptor gamma agonists and related therapeutic methods |
| WO2015171558A2 (en) | 2014-05-05 | 2015-11-12 | Lycera Corporation | BENZENESULFONAMIDO AND RELATED COMPOUNDS FOR USE AS AGONISTS OF RORγ AND THE TREATEMENT OF DISEASE |
| JP6728061B2 (en) | 2014-05-05 | 2020-07-22 | リセラ・コーポレイションＬｙｃｅｒａ Ｃｏｒｐｏｒａｔｉｏｎ | Tetrahydroquinoline sulfonamide and related compounds for use as RORγ agonists and treatment of diseases |
| EP3292119A4 (en) | 2015-05-05 | 2018-10-03 | Lycera Corporation | DIHYDRO-2H-BENZO[b][1,4]OXAZINE SULFONAMIDE AND RELATED COMPOUNDS FOR USE AS AGONISTS OF RORy AND THE TREATMENT OF DISEASE |
| US10611740B2 (en) | 2015-06-11 | 2020-04-07 | Lycera Corporation | Aryl dihydro-2H-benzo[b][1,4]oxazine sulfonamide and related compounds for use as agonists of RORγ and the treatment of disease |
| CN113735931B (en) * | 2021-08-27 | 2022-06-14 | 浙江花园营养科技有限公司 | Method for separating cholesterol and 24-dehydrocholesterol by complexing crystallization |
-
1972
- 1972-07-27 DE DE2236930A patent/DE2236930A1/en not_active Ceased
- 1972-07-27 NL NL7210355A patent/NL7210355A/xx not_active Application Discontinuation
- 1972-07-28 FR FR7227356A patent/FR2149796A5/fr not_active Expired
- 1972-07-31 GB GB35717/72*2A patent/GB1355272A/en not_active Expired
- 1972-08-01 BE BE787024A patent/BE787024A/en unknown
- 1972-08-02 CH CH1154872A patent/CH582714A5/xx not_active IP Right Cessation
- 1972-08-03 JP JP47078017A patent/JPS5241260B2/ja not_active Expired
- 1972-08-03 US US00277841A patent/US3803184A/en not_active Expired - Lifetime
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101270141B (en) * | 2008-04-16 | 2010-12-01 | 浙江大学 | Method for separating 24-dehydrogenation cholesterol and cholesterol |
Also Published As
| Publication number | Publication date |
|---|---|
| CH582714A5 (en) | 1976-12-15 |
| JPS5241260B2 (en) | 1977-10-17 |
| GB1355272A (en) | 1974-06-05 |
| US3803184A (en) | 1974-04-09 |
| FR2149796A5 (en) | 1973-03-30 |
| BE787024A (en) | 1972-12-01 |
| JPS4885564A (en) | 1973-11-13 |
| NL7210355A (en) | 1973-02-06 |
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